<i>Mycobacterium tuberculosis</i> Effects on Fibroblast Collagen Metabolism

Abstract

Background: Type I collagen synthesis and degradation are important events during Mycobacterium tuberculosis (MTb) granuloma or cavity formation, and fibroblasts are cells involved in these processes. Objective: We examined the MTb effects on fibroblast collagen metabolism to understand the virulence factors involved in tuberculosis pathogenesis. Methods: Human lung fibroblasts were incubated with culture medium or sonicated MTb H37Ra (avirulent) or H37Rv (virulent) strains. The effects on collagen synthesis, fibroblast proliferation and collagenase activity were examined. Matrix metalloproteinase-1 (MMP-1), MMP-13 and tissue inhibitors of metalloproteinases (TIMP-1) mRNA levels were analyzed by quantitative real-time PCR amplification. Protein expression was explored by Western blot technique. Results: Collagen synthesis and fibroblast proliferation were significantly increased by H37Ra medium. In contrast, cells incubated with H37Rv medium showed an increase in collagenase activity. MMPs quantitative real-time PCR amplification revealed an increase on MMP-13 mRNA levels in fibroblasts cultured with H37Rv medium, with little effect observed on MMP-1 expression. Western blot assay demonstrated that H37Rv medium stimulated MMP-1 and MMP-13 proenzyme synthesis. This medium had a large effect on MMP-1 activation. TIMP-1 transcription was increased in cells incubated with medium and sonicated from H37Ra, although the highest TIMP-1 protein expression was found in fibroblasts cultured with sonicated H37Rv. Conclusions: These results suggest that MTb had direct effects on fibroblast collagen turnover, with differences in collagen synthesis and degradation depending on the strain.

Histopathological Findings in Immunohistological Staining of the Granulomatous Tissue Reaction Associated with Tuberculosis

“…Recent studies are also indicative of the active role of endothelial cells in immunologic tissue reactions [17]. Furthermore, the role of plasma cells [18] and fibroblasts [19] alongside the main cells in cell-mediated immune response to TB is a matter of discussion.…”

ESX-5-deficient Mycobacterium marinum is hypervirulent in adult zebrafish

“…The rapid development of granulomas and eventual tissue destruction in zebrafish infected with the ESX‐5‐deficient M. marinum correlates with the prolonged induction of the tissue remodelling genes mmp9 and mmp13 . These genes encode matrix metalloproteinases that have been suggested to be involved in granuloma formation during mycobacterial infection (Taylor et al ., 2006; Gonzalez‐Avila et al ., 2009; van der Sar et al ., 2009). The large increase in transcription of ifn‐γ , tnf‐α and il‐1β after 2 weeks indicates high levels of inflammation induced by the rapidly progressing infection, which probably leads to tissue damage rather than effective bacterial clearance.…”

Mycobacterium tuberculosis infection of the ‘non‐classical immune cell’

“…Fibroblast responses may well be regulated by mycobacterial virulence. Whereas infection with less virulent H37Ra resulted in the stimulation of collagen synthesis, virulent H37Rv promoted collagen degradation, the latter process ascribed as a prerequisite for cavity formation and mycobacterial dissemination 62 . M. tuberculosis can actively upregulate MMP‐1 in a STAT 3‐, p38 MAPK‐ and NF‐kappaB‐dependent manner, thereby promoting cleavage of collagen 63 .…”

“…17 While having the capacity to directly kill M. tuberculosis, epithelial cells can assist pulmonary macrophages to enhance its antibactericidal functions in a NO-independent manner. 28 15,51 and fibroblasts, [61][62][63][64]67 are able to induce immune responses by secreting immune modulators. M. tuberculosis bacilli can disseminate from the lung into the central nervous system and the rest of the body.…”